Heterozygous germline mutations in the bone morphogenetic protein type II receptor gene (BMPRII) are associated with hereditary pulmonary arterial hypertension (HPAH). Missense mutations, both in the extracellular ligand-binding and cytoplasmic kinase domains, mostly involve substitution of conserved Cys residues. Singular substitution at any of those Cys residues causes cytoplasmic, perinuclear localization of BMPR with reduced cell surface expression and BMP signaling. The present study examined the effect of Cys residue substitution on BMPR endocytic trafficking and lysosome degradation. We demonstrate that endocytosis/lysosomal degradation of BMPR occurs by two distinct pathways. SMURF1 ubiquitin ligase induces lysosomal degradation of BMPR, while ligase-inactive SMURF1 maintains BMPR protein level and cell surface expression. Substitution of BMPR Cys residues increases lysosomal degradation which is blocked by ligase-inactive SMURF1, elevating protein levels of Cys-substituted BMPRs. Expression of Cys-substituted BMPR suppresses basal BMP signaling activity which is also up-regulated by ligase-inactive SMURF1. Cys-residue substitution thus appears to cause BMPR endocytosis to lysosomes in a SMURF1 ubiquitin ligase-associated pathway. Kinase-activated BMPR undergoes endocytic/lysosomal degradation by a pathway with certain unique properties. Therefore, our results describe a novel mechanism whereby SMURF1 ubiquitin ligase regulates constitutive endocytosis of BMPR which may be mediated by its conserved Cys residues.

骨形态发生蛋白II型受体基因（BMPRII）中的杂合种系突变）与遗传性肺动脉高压（HPAH）相关。细胞外配体结合域和胞质激酶域中的错义突变都主要涉及保守的Cys残基的取代。在那些Cys残基中的任何一个上进行单数取代都会导致BMPR的胞质，核周定位，并降低细胞表面表达和BMP信号传导。本研究检查了Cys残基取代对BMPR内吞运输和溶酶体降解的影响。我们证明了BMPR的内吞/溶酶体降解是通过两种不同的途径发生的。SMURF1泛素连接酶诱导BMPR的溶酶体降解，而无连接酶的SMURF1维持BMPR蛋白水平和细胞表面表达。取代BMPR Cys残基会增加溶酶体降解，这种降解被连接酶失活的SMURF1阻止，升高半胱氨酸取代的BMPRs的蛋白质水平。Cys取代的BMPR的表达抑制了基础BMP信号传导活性，该活性也被无连接酶的SMURF1上调。因此，Cys残基取代似乎在SMURF1泛素连接酶相关途径中导致BMPR内吞到溶酶体。激酶激活的BMPR通过具有某些独特特性的途径经历内吞/溶酶体降解。因此，我们的结果描述了一种新的机制，其中SMURF1泛素连接酶调节BMPR的组成型内吞作用，其可能由其保守的Cys残基介导。因此，在SMURF1泛素连接酶相关途径中，Cys残基取代似乎导致BMPR内吞到溶酶体。激酶激活的BMPR通过具有某些独特特性的途径经历内吞/溶酶体降解。因此，我们的结果描述了一种新的机制，其中SMURF1泛素连接酶调节BMPR的组成型内吞作用，其可能由其保守的Cys残基介导。因此，在SMURF1泛素连接酶相关途径中，Cys残基取代似乎导致BMPR内吞到溶酶体。激酶激活的BMPR通过具有某些独特特性的途径经历内吞/溶酶体降解。因此，我们的结果描述了一种新的机制，其中SMURF1泛素连接酶调节BMPR的组成型内吞作用，其可能由其保守的Cys残基介导。